JPS635014B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an aid for promoting transdermal absorption of drugs, an external pharmaceutical composition containing the absorption aid, and a method for promoting transdermal absorption of drugs. Conventionally, when administering drugs to the outer skin, sterilization, disinfection,
They were intended to act locally on the outer skin or its subcutaneous tissue, such as analgesic, antipruritic, and antiinflammatory. Furthermore, when a systemic effect is desired, administration has conventionally been carried out through oral tablets or injections.
Oral tablets have the disadvantage that they are susceptible to primary hepatic injection after absorption, that absorption is insufficient, and that the concentration in the body is higher than is initially necessary to maintain the effect. Ta. In some cases, oral administration, such as indomethacin, causes gastrointestinal disorders. On the other hand, administration by injection allows rapid absorption, but requires a specialist such as a doctor. In recent years, in order to improve the above-mentioned side effects and disadvantages, transdermal administration methods aiming at systemic effects have been proposed. When a drug is administered transdermally, there are advantages such as the ability to easily maintain drug efficacy, the ability to control the concentration of the drug in the body, and the fact that the drug enters the bloodstream through the skin tissue, making it less susceptible to primary hepatic toxicity. However, since normal skin inherently has a barrier function to prevent foreign substances from entering the body, administration of medicines through the skin has been limited to topical applications. Therefore, when a systemic effect is intended, a transdermal absorption promoting aid is necessary, and various kinds of aids have been proposed in recent years. For example, U.S. Pat.
No. 3551554 contains dimethyl sulfoxide,
Dimethylacetamide, dimethylformamide, methyldecyl sulfoxide, etc. are disclosed. In addition, dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl palmitate, etc. (US Patent No. 3472931) are used as absorption promoting agents in combination with lower alkylamide.
There are examples of combinations of 2-pyrrolidone, appropriate oils, and esters of straight-chain aliphatic acids and alcohols (US Pat. No. 4,017,641), but these absorption-enhancing aids are lacking in terms of efficacy, safety, and usability. It's still not enough. As a result of intensive research into methods for promoting transdermal absorption of drugs, the present inventors found that an aliphatic hydrocarbon ester of 2-pyrrolidone-5-carboxylic acid, a natural amino acid, improves skin permeability and transdermal absorption of drugs. It has been found that the hydrocarbon esters of pyrrolidone carboxylic acid can be used as a component of a base in formulating drugs that can be applied to the skin. The present invention was completed based on the above-mentioned new findings, and its first purpose is to provide an aid for promoting transdermal absorption of drugs. A second object of the present invention is to provide an external pharmaceutical composition with good skin permeability and transdermal absorption of drugs. A third object of the present invention is to provide a method for increasing skin permeability and percutaneous absorption of drugs. That is, the present invention provides transdermal absorption of drugs containing at least one ester compound selected from aliphatic hydrocarbon esters of 2-pyrrolidone-5-carboxylic acid (hereinafter referred to as pyrrolidocarboxylic acid esters) as an absorption-promoting active ingredient. This is a pharmaceutical composition for external use, characterized by containing a promoting aid, at least one ester compound selected from pyrrolidone carboxylic acid esters, and a drug for external administration. Pyrrolidone carboxylic acid or its sodium salt is conventionally known as an emollient agent and is used in cosmetics. In addition, esters of pyrrolidone carboxylic acid can be used as non-aqueous surfactants,
Examples include textile softeners and emulsion stabilizing agents. However, it was not expected that the hydrocarbon ester of pyrrolidone carboxylic acid would promote transdermal absorption of drugs. Examples of pyrrolidone carboxylic acid esters include alkyl esters and unsaturated hydrocarbon esters. The alkyl in the alkyl ester may be cyclic, ie, cycloalkyl, and may be either linear or branched. Furthermore, the unsaturated hydrocarbon group in the unsaturated hydrocarbon ester may be linear, branched, or cyclic. Specifically, as the chain alkyl ester,
Pyrrolidonecarboxylic acid methyl ester, pyrrolidonecarboxylic acid ethyl ester, pyrrolidonecarboxylic acid n-propyl ester, pyrrolidonecarboxylic acid n-butyl ester, pyrrolidonecarboxylic acid n
-Heptyl ester, pyrrolidone carboxylic acid n-
Octyl ester, pyrrolidonecarboxylic acid n-nonyl ester, pyrrolidonecarboxylic acid n-decyl ester, pyrrolidonecarboxylic acid n-undecyl ester, pyrrolidonecarboxylic acid n-dodecyl ester, pyrrolidonecarboxylic acid n-tridecyl ester, pyrrolidonecarboxylic acid n- Tetradecyl ester, pyrrolidonecarboxylic acid n-hexadecyl ester, pyrrolidonecarboxylic acid n-octadecyl ester, pyrrolidonecarboxylic acid n-eicosyl ester, pyrrolidonecarboxylic acid iso-propyl ester, pyrrolidonecarboxylic acid 2-methylhexyl ester, pyrrolidonecarboxylic acid 2-ethylhexyl ester, pyrrolidonecarboxylic acid 3,7-dimethyloctyl ester, pyrrolidonecarboxylic acid 2-hexyldecyl ester, pyrrolidonecarboxylic acid 2-octyldodecyl ester,
2,4,4-trimethyl pyrrolidonecarboxylate 1-
Straight chain and branched ones such as pentane ester and pyrrolidone carboxylic acid methyloctyl ester are mentioned, and the alkyl moiety of the alkyl ester preferably has 1 to 20 carbon atoms. Examples of the cyclic alkyl ester include pyrrolidonecarboxylic acid 2-cyclohexyl ethyl ester, pyrrolidonecarboxylic acid cycloheptyl ester, pyrrolidonecarboxylic acid cyclohexylmethyl ester, pyrrolidonecarboxylic acid cyclooctyl ester, pyrrolidonecarboxylic acid 4-cyclohexylbutyl ester, and pyrrolidonecarboxylic acid 3- Examples include cyclopentylpropyl ester, pyrrolidonecarboxylic acid 5-methyl-2-isopropylclohexyl ester, and the cyclic alkyl ester preferably has 6 to 12 carbon atoms in the alkyl moiety. Examples of unsaturated hydrocarbon esters include pyrrolidonecarboxylic acid-Cis-3-hexenyl ester, pyrrolidonecarboxylic acid-oleyl ester, pyrrolidonecarboxylic acid linoleyl ester, and the number of carbon atoms in the hydrocarbon portion of the hydrocarbon ester is 6. ~24 are preferred. Further examples of unsaturated hydrocarbon esters include esters derived from terpene alcohols, such as pyrrolidone carboxylic acid geranyl ester, in which case the number of carbon atoms in the terpene alcohol is
It is preferably 10-20. In the absorption promoting aid of the present invention, hydrocarbon esters having 6 or more carbon atoms are generally used together with highly polar hydrophilic compounds, and hydrocarbon esters having 1 to 5 carbon atoms are generally non-polar hydrophobic compounds. By using it in combination with a sexual compound, the absorption promoting effect can be further enhanced. Examples of the hydrophilic base include the following. Lower alcohols: Specifically, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol, iso-amyl Those having 1 to 5 carbon atoms, such as alcohol, are listed as preferred. Glycerin and its ester: The ester may be mono-, di- or triester, and the acid component is preferably a fatty acid having 2 to 6 carbon atoms, particularly acetic acid. Specific examples include glycerin monoacetate, glycerin diacetate,
Glycerin triacetate and the like are listed. Thioglycerol: Any of mono-, di-, or triglycerol may be used, such as α-monothioglycerol. Lactic acid, its ester: As the alcohol moiety in the ester, an aliphatic monohydric alcohol having 1 to 4 carbon atoms is preferred.
Specific examples include lactic acid, methyl lactate, ethyl lactate, and butyl lactate. Cyclic urea: Preferably a 5- or 6-membered ring, specifically N,N'-dimethylethyleneurea, ethyleneurea,
Examples include propylene urea. general formula [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are each a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, iso-propyl, n-butyl, etc.), nitro or Indicates acyl having 1 to 2 carbon atoms. ] Compounds represented by: Specifically, urea, N-methylurea, N-ethylurea, N-butylurea, 1,1-dimethylurea,
1,3-dimethylurea, 1,1-diethylurea,
1,3-diethylurea, 1,1,3,3-tetramethylurea, N-acetyl-N'-methylurea,
Nitrourea etc. are listed. general formula [In the formula, R ₅ is a hydrogen atom or a lower alkyl having 1 to 3 carbon atoms (methyl, ethyl, n-propyl,
iso-propyl, etc.), n represents an integer of 3 to 5. ] Compounds represented by: Specifically, 2-pyrrolidone, N-methylpyrrolidone, N-methylpiperidone, caprolactam,
N-methylcaprolactam and the like are listed. general formula [In the formula, R ₆ , R ₇ and R ₈ are each a hydrogen atom,
Alkyl having 1 to 3 carbon atoms (methyl, ethyl, n-
propyl, iso-propyl, etc.). ] Compounds represented by: Specifically, formamide, N-methylformamide, N,N-dimethylformamide, N,N
-diethylformamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, N,N-diethylacetamide, propionamide, N-methylpropionamide, N,N-
Dimethylpropionamide, N,N-diethylpropionamide and the like are listed. Alkylene glycol: Alkylene preferably has 2 to 8 carbon atoms, specifically ethylene glycol, 1,3
-Propanediol, 1,2-propanediol, butanediol, pentanediol, 2-methyl-2,4-pentanediol, 2-ethyl-
1,3-hexanediol and the like are listed. Monoalkyl ether of mono- or diethylene glycol: The alkyl in the monoalkyl ether preferably has 1 to 2 carbon atoms. in particular,
Examples include ethylene glycol monomethyl ether and ethylene glycol monoethyl ether. Lactone: Specific examples include propiolactone, butyrolactone, and β-butyrolactone. Examples of the hydrophobic base include linear alcohols, branched alcohols, and unsaturated alcohols having 7 to 20 carbon atoms. 5 or more carbon atoms which may be substituted with halogen
30 linear, branched or cyclic aliphatic hydrocarbons: As the halogen as a substituent, brome and chloro are preferred. The aliphatic hydrocarbon moiety is preferably an alkyl group having 5 to 30 carbon atoms (preferably 6 to 24 carbon atoms) or having 1 or 2 unsaturated bonds in the case of a chain structure, and a monocarbon alkyl group in the case of a cyclic structure. Rings and two-membered rings are preferred. In the case of a monocyclic ring, the number of carbon atoms is preferably 6 to 10, and it is one or more methyl,

It may be substituted with a saturated or unsaturated alkyl having 1 to 3 carbon atoms such as [Formula]. Alternatively, two or more monocycles may be bonded via an alkylene. In the case of a two-membered ring, it preferably has 10 to 12 carbon atoms, which may be substituted with, for example, one or more lower alkyl such as methyl. Specifically, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-
-Undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-
Methyl-pentane, 2-methylhexane, 2,3
-dimethylhexane, 2-methylnonane, 2,6
-dimethyloctane, 2,2,4,4,6,8,
8-heptamethylnonane, pristane, squalane, light liquid paraffin, paramethane, limonene, hydrogenated product of limonene dimer, cyclohexane, 1,3-dimethylcyclohexane, cyclooctane, isobutylcyclohexane, cyclododecane, methyldecalin, decalin, octyl bromide , decyl bromide, dodecyl bromide, hexadecyl bromide, dodecyl chloride, dibromidodecane, and the like. Alcohol ester of aliphatic carboxylic acid having a total carbon number of 1 to 26: The alcohol moiety is methyl alcohol, ethyl alcohol, n-propyl alcohol, iso
-Propyl alcohol, n-butyl alcohol,
Monohydric alcohols having 1 to 6 carbon atoms such as iso-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-amyl alcohol, iso-amyl alcohol, and n-hexyl alcohol are listed as preferred. Further, as the carboxylic acid moiety, a fatty acid having 10 to 20 carbon atoms, particularly a saturated fatty acid having 12 to 18 carbon atoms is preferable. Specific examples of the ester include methyl laurate, ethyl laurate, hexyl laurate, isopropyl myristate, isopropyl palmitate, methyl stearate, and butyl stearate. Mono- or diether having 10 to 24 carbon atoms: specifically dithyl ether, dihexyl ether, dioctyl ether, didodecyl ether,
Examples include alkyl monoethers such as methoxydodecane and ethoxydodecane, ethers having an alicyclic ring such as 1,8-cineole, and alkyl diethers such as ethylene glycol dibutyl ether, ethylene glycol dipropyl ether, and ethylene glycol dioctyl ether. Ketones having 11 to 15 carbon atoms: aliphatic ketones are preferred, such as 2-undecanone, 3-undecanone, 4-undecanone,
5-undecanone, 6-undecanone, 3-dodecanone, 4-dodecanone, 5-dodecanone, 2-
Examples include tridecanone, 3-tridecane, 7-tridecanone, 8-pentadecanone, and 3-hexadecanone. The blending ratio of pyrrolidone carboxylic acid ester and the hydrophilic or hydrophobic compound is 99:1 by weight.
~1:99. There are no particular restrictions on the drug to be mixed into the external preparation of the present invention, as long as it can be administered to the skin.If the drug is intended for local action, the drug is intended to penetrate deep into the body, and the drug is intended for systemic action. In the case of,
The drug quickly moves into the blood. Specifically, local drugs include local anesthetics (e.g., procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, piperocaine acetate), antihistamines (e.g., diphenyhydramine hydrochloride, chlorphene maleate), niramine, brompheniramine maleate, diphenylimidazole, clemizole hydrochloride), antibiotics (e.g., lincomycin, penicillin G, erythromycin, tetracycline hydrochloride, clindamycin, kanamycin, oxytetracycline,
chloramphenicol, fradiomycin, nystatin, gramicidin hydrochloride, bacitracin),
Antifungal agents [e.g. griseofulvin, N-methyl-
N-(3-tolyl)thiocarbamic acid-2-naphthyl ester, diamethazole hydrochloride, oleothricin, trichomycin, pyrrolenitrile, 5-
Fluorocytosine] etc. Specific examples of systemic drugs include benzodiazepines (e.g. diazepam, nitrazepam, flunitrazepam, lorazepam, prazepam, fludiazepam, clonazepam), diuretics [e.g. thiazides (e.g. bendroflumethiazide, polythiazide, methyclothiazide) , trichlormethiazide, cyclopenthiazide, benzylhydrochlorothiazide, hydrochlorothiazide, bumetanide),
Antihypertensive drugs (e.g., clonidine), antihistamines [e.g.,
aminoethers (e.g., diphenhydramine, carbinoxamine, diphenylpyraline), ethylenediamines (e.g., phebenzamine), monoamines (e.g., chlorpheniramine)], nonsteroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibufuenatuk, alclofenatuk, diclofenatuk, mefenamic acid, flurpiprofen, flufenamic acid, ketoprofen), antineoplastic agents [e.g., 5-fluorouracil, 1-(2)
-tetrahydrofuryl) -5-fluorouracil, cytarabine, broxuridine], steroid anti-inflammatory agents (e.g., cortisone, hydrocortisone, prednisolone, prednisone, triamcinolone, dexamethasone, betamethasone), antiepileptic agents (e.g., ethosuximide), antiarrhythmia agents (e.g. ajmarine, pradimarine, pindolol,
Propranolol, Quinidine) Neuropsychiatric agents (e.g. clofluperiol, trifluperidol,
haloperidol, moperon), scopolamines (e.g., methylscopolamine, butylscopolamine), chloropromazine, atropines (e.g., methylatropine bromide, methylanisotropine bromide), vasodilators (e.g. isosorbit dinitrate) , nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole), antibiotics [e.g., tetracyclines, (e.g.,
Examples include tetracycline, oxytetracycline, methacycline, doxycycline, minocycline), chloramphenicols, and erythromycins. The amount of the drug to be mixed may be an amount sufficient to achieve the desired medicinal effect, and the amount varies depending on the type of drug, patient's weight, symptoms, etc., and may be appropriately selected depending on these conditions. In general,
It is preferably 0.01 to 20% by weight, particularly 0.2 to 10% by weight, based on the total amount of pyrrolidone carboxylic acid ester and other base materials. Note that the amount of the drug to be used can be adjusted by increasing or decreasing the area of the pharmaceutical composition applied to the skin, so it is not necessarily limited to the above-mentioned amount. The external pharmaceutical composition according to the present invention can be used as it is or with the addition of a known pharmaceutically acceptable third component to ointments, plasters, lotions, adhesive tapes, etc.
It is administered to the skin as a non-emulsifying external preparation such as an impregnation agent or gel. Examples of impregnating agents include those obtained by adsorbing the topical pharmaceutical composition or a composition containing a known third component onto a suitable adsorbent (gauze, filter paper, porous membrane, etc.),
It is commonly applied to the skin by securing with surgical adhesive tape. In addition, as a gel agent, for example, dipendylidene sorbitol [e.g.
Gelol D) manufactured by Shin Nippon Rika Co., Ltd.)] is used to form a gel, and the gel is spread on a support. In addition, examples of the adhesive base for the adhesive tape include those known per se, such as acrylic copolymers, polyvinyl ether compounds, and rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se. The present invention will be explained in more detail below using Examples and Experimental Examples, but the present invention is not limited thereto. Manufacturing example 1 Structural formula Production of 2-pyrrolidone-5-carboxylic acid n-heptyl ester having: 6.5 g of 2-pyrrolidone-5-carboxylic acid
(0.05mol), n-heptyl alcohol 23.2g
(0.20 mol), a catalytic amount of concentrated sulfuric acid, and 40 ml of benzene were placed in a 200 ml eggplant-shaped colben equipped with a condenser and a mechanical stirrer, and refluxed for 3.5 hours. After cooling to room temperature, pour into saturated _NaHCO3 water and extract with benzene.
Wash and dry in a conventional manner, remove the solvent, and distill under reduced pressure to obtain a yellow 2-pyrrolidone-5-carboxylic acid n-
7.4 g of heptyl ester was obtained. Boiling point 186-188
℃/3mmHg. Other pyrrolidone carboxylic acids are also produced according to Production Example 1 above. Examples 1 to 16 Basic formulation (1) Drug 1% by weight (2) Hydrophilic or hydrophobic compound 74% by weight (3) Pyrrolidone carboxylic acid ester 25% by weight (1), (2) and (3) in Table 1 Using each of the ingredients shown in (3) to (2), the liquid composition with the above basic formulation was prepared.
The mixture was mixed with the following ingredients and further prepared by dissolving (1). Control formulation 1 (1) Drug: 1% by weight (2) Hydrophilic or hydrophobic compound: 99% by weight (2) Using those listed in the examples in Table 1, (1) was dissolved in (2). A composition was obtained by removing component (3) from each Example. Comparative Examples 1 to 5 (1) Drug 1% by weight (2) Hydrophilic or hydrophobic compound 74% by weight (3) Pyrrolidone carboxylic acid monoglyceride ester 25% by weight (R is oleic acid or stearic acid residue) Examples 17-28 Basic formulation (1) Drug 1% by weight (2) Hydrophilic or hydrophobic compound 24% by weight (3) Pyrrolidone carboxylic acid ester 75% by weight (1) , (2) and (3) shown in Table 1, the liquid composition with the above basic formulation was first mixed with (3) and (2).
The mixture was mixed with the following ingredients and further prepared by dissolving (1). Comparative Examples 6 to 10 (1) Drug 1% by weight (2) Hydrophilic or hydrophobic compound 24% by weight (3) Pyrrolidone carboxylic acid or sodium salt
75% by weight Experimental Example 1 The amount of drug permeated through the skin of the compositions of Examples 1 to 28, Control Formulation 1, and Comparative Examples 1 to 10 was measured using excised abdominal skin of rats, and the results are shown in Tables 1 and 1. Shown in 2. Note that the Q values in Tables 1 and 2 mean the following. Q=C/D C: Amount of drug permeated through the skin in Examples or Comparative Examples D: Amount of drug permeated through the skin in Control Formulation 1 (Measurement method) A portion corresponding to the front side of the skin is in contact with the above composition, and a portion corresponding to the back side of the skin is in contact with the above composition. The rat skin was attached to a glass transmission cell so that the exposed area was in contact with the saline, and the drug that had permeated into the saline was quantified using high performance liquid chromatography. Note that this experiment was conducted in a sealed container. Example 29/Experimental Example 2 (1) Propranolol hydrochloride 1g (2) 1,2-propanediol 0-100g (3) Pyrrolidonecarboxylic acid-n-dodecyl ester 100-0g Component (2) and component (3) The mixing ratio (weight ratio) of
Mixtures varying in ratio from 100:0 to 0:100 were prepared, and propranolol hydrochloride was dissolved therein to give a composition of 1%. The skin permeability of each composition thus obtained was measured in the same manner as in Experimental Example 1, and is shown in FIG. In Figure 1, the Y axis represents the permeability of the drug in each of the above mixed solutions when using component (2) alone (100 g) as the base, and the X axis represents the permeability of the drug relative to the sum of components (2) and (3).
(3) The weight percent of the components is shown. Example 30/Experimental Example 3 (1) Propranolol hydrochloride 1g (2) Dragosantol 0-100g (3) Pyrrolidone carboxylic acid methyl ester
100~0g Mixing ratio (weight ratio) of component (2) and component (3)
Mixtures varying in ratio from 100:0 to 0:100 were prepared, and propranolol hydrochloride was dissolved therein to give a composition of 1%. The skin permeability of each composition thus obtained was measured in the same manner as in Experimental Example 1, and is shown in FIG. In Figure 2, the Y-axis represents the drug permeability in each of the above mixed solutions when using component (2) alone (100 g) as the base, and the X-axis represents the permeability of the drug relative to the sum of components (2) and (3).
(3) The weight percent of the components is shown. However, Dragosantol is manufactured by Nippon Drabco, α-bisabolol 85%,
Falnesol is 15%.

[Brief explanation of the drawing]

FIGS. 1 and 2 are graphs showing the effects of the present invention.

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Claims (1)

[Scope of Claims] 1. An auxiliary agent for promoting transdermal absorption of drugs, which contains at least one ester compound selected from aliphatic hydrocarbon esters of 2-pyrrolidone-5-carboxylic acid as an absorption-promoting active ingredient. 2. An external pharmaceutical composition comprising at least one ester compound selected from aliphatic hydrocarbon esters of 2-pyrrolidone-5-carboxylic acid and a drug for external administration.